tbuckley/cabot-search huggingface dataset:
The CDK4/6 inhibitor FCN-437c plus letrozole for the treatment of HR+/HER2– advanced breast cancer: Updated results from a phase 1b study.
Authors: Jian Zhang, Xiaojia Wang, Xian Wang, Wei Li, Ying Cheng, Tao Huang, Ying Wang, Ai-Min Hui, Zhuli Wu, Ling Tian, Han Zhao, Yuchen Yang, Wenjing Zhang, Yushun Zhang, Xichun Hu
Journal: Journal of Clinical Oncology (2022)

e13025 Background: FCN-437c is an oral potent and highly selective CDK4/6 inhibitor without the inhibition of CDK1, CDK2, or CDK5. In the phase 1a dose-escalation part of this study (NCT04488107), the safety profile of FCN-437c was acceptable in patients with ABC, and the maximum tolerated dose was determined to be 300 mg QD when used as monotherapy (presented at AACR 2021). Phase 1b aimed to explore the RP2D and to evaluate the tolerability and antitumor activity of FCN-437c combined with letrozole in patients with previously untreated HR+/HER2– ABC. Methods: Adult, post-menopausal female patients diagnosed with treatment-naive ER+/HER2– ABC were eligible for this expansion stage. Patients received FCN-437c once daily at 200 mg or 300 mg on a 21-day-on and 7-day-off schedule in combination with letrozole 2.5 mg once daily in 28-day cycles. The primary endpoints were safety and RP2D. Results: As of November 26, 2021, 29 patients were enrolled and had a median follow-up of 10.4 months. Of these patients, 25 (86.2%) were endocrine-sensitive and 4 (13.8%) were endocrine-resistant. Visceral disease was present in 21 patients (72.4%), and 1 (3.4%) patient had bone-only disease. DLTs of grade 4 neutropenia occurred in 2 patients (40.0%) in 300 mg dose group; they were considered intolerable. One out of the first 6 patients experienced DLTs in 200 mg dose group (grade 4 neutropenia, leukopenia, and thrombocytopenia); these were also considered to be FCN-437c-related SAEs. FCN-437c-related grade ≥3 TEAEs were observed in 26 (89.7%) patients, with neutropenia (n=24, 82.8%) and leukopenia (n=14, 48.3%) being most common. Among the 28 measurable patients, 16 patients had a PR, the ORR was 57.1% (95% CI 37.2–75.5); the CBR was 82.1% (95% CI 63.1–93.9) (Table). Median PFS, DOR, and OS were not reached. At 6 and 12 months, PFS rates were 92.3% and 83.5%, and DOR rates were 100% and 90%, respectively. A RP2D of 200 mg was suggested per safety considerations and preliminary antitumor activity. Conclusions: FCN-437c plus letrozole was well tolerated and demonstrated antitumor activity in patients with previously untreated HR+/HER2– ABC. FCN-437c in combination with NSAI as the first-line treatment for HR+/HER2– ABC will be further investigated in a phase 3 trial. Clinical trial information: NCT04488107. [Table: see text]
The association between mediators of the receptor for advanced glycation end product (RAGE) axis and immune checkpoint inhibitor (ICI)–induced colitis in patients with melanoma.
Authors: Morgan Simons, Michaele Manigrasso, Xiaochun Li, Judith Goldberg, Iman Osman, Ann Marie Schmidt
Journal: Journal of Clinical Oncology (2022)

9587 Background: Colitis and other gastrointestinal (GI) toxicity are a frequent and occasionally severe form of immune-related adverse events (irAEs) in patients treated with ICIs. To date, no definitive mechanism has been identified, and this area remains an active field of investigation. We hypothesized that activation of the RAGE axis, known to be implicated in inflammatory bowel disease through stimulation of signal transduction targeted by pro-inflammatory RAGE ligands, members of the S100 family and High Mobility Group Box 1 (HMGB1), might be associated with irAE- colitis. Methods: We examined sera from 111 advanced melanoma patients prospectively accrued and followed up at NYULH (treated with anti-PD-L1, n = 44; antiCTL4, n = 23; and combination, n = 44). 24 (22%) developed GI toxicity grade &gt;2. Serum biomarkers of the ligand-RAGE pathways, soluble (s)RAGE, endogenous secretory (es)RAGE, S100B, and HMGB1, were measured in the patients’ sera during ICI treatment. Multivariable ordinal logistic regression analyses with all grades of GI toxicity as the primary outcome for all the recorded covariates (including serum biomarkers, clinical covariates) were performed. We then used ordinal multivariable logistic regression with stepwise variable selection. Similar analyses with GI toxicity as a binary outcome ((≥grade 1 vs no toxicity) were also conducted. Only those variables that jointly contributed to the odds of developing toxicity were included in the final stepwise model. No adjustments for multiplicity were included. As sRAGE and esRAGE are highly correlated (r = 0.86), esRAGE concentrations were not used in the joint models. Results: A significant association between GI toxicity and concentrations of sRAGE and S100B was identified. The final stepwise multivariable logistic model includes only sRAGE and S100B. The odds of having a one level increase in GI toxicity grade increase 1.100 times (95% CI: 1.008, 1.199; p = 0.029) for each unit decrease of sRAGE ( = sRAGE/100). The odds of a one level increase in GI toxicity increase 1.059 times (95% CI: 1.004, 1.116; p = 0.035) for each unit increase of S100B ( = s100B/100). All other analyses yielded comparable results. In contrast, concentrations of HMGB1 and other clinical covariates, including response and treatment category, were not associated with GI toxicity. Conclusions: Mediators of the RAGE axis, specifically sRAGE and S100B, might have a role in GI toxicity in patients receiving ICIs. The ligand-RAGE axis may be a novel target for irAE therapies for patients receiving ICIs to mitigate the severity of GI toxicity.
Phase II trial of gemcitabine and nab-paclitaxel for recurrent osteosarcoma: A report from the National Pediatric Cancer Foundation.
Authors: Lars M. Wagner, Leo Mascarenhas, Michael Isakoff, Bhuvana Setty, Joanne P. Lagmay, Emi Caywood, Eric Stuart Sandler, Christine A. Pratilas, Scott C. Borinstein, Matteo M. Trucco, Brooke Fridley, Damon R. Reed, Javier E. Oesterheld
Journal: Journal of Clinical Oncology (2022)

10042 Background: The combination of gemcitabine and docetaxel is often used to treat patients with recurrent osteosarcoma. A retrospective study of 35 such patients has reported an objective response rate of 17% and 4-month progression-free survival (PFS) of 56% with this combination (BMC Cancer 2016;16:280). Nab-paclitaxel is a nanoparticle taxane that has activity against osteosarcoma xenografts and may have less myelosuppression than docetaxel. The combination of gemcitabine and nab-paclitaxel is now frontline therapy for pancreatic cancer. We conducted a prospective multi-institutional phase II trial of this drug combination for patients with recurrent osteosarcoma. Methods: Patients with relapsed/refractory osteosarcoma with measurable disease and age ≥ 12 years and adequate organ function were included. A Simon’s two-stage design was used to identify a 4-month progression-free survival (PFS) of &gt; 35%. Patients received nab-paclitaxel 125 mg/m 2 and gemcitabine 1000 mg/m 2 weekly x 3 in 4-week cycles. Results: Eighteen patients with a median age 16 years (range 12- 26) received a total of 56 total cycles.(median 2, range 1 - 12). The median number of prior treatment regimens was 3 (range 1-7). Two patients (11%) experienced a partial response, and 6 (33%) received more than 2 cycles. The 4-month PFS was 30% (95% CI 14-62 %). Six patients required dose reductions for neutropenia (n = 4), pleural effusion (1), or neuropathy (1). Two patients were removed from study secondary to neutropenia despite dose reduction and myeloid growth factor support, and one patient came off study due to severe peripheral edema. Conclusions: In this prospective study, the combination of gemcitabine and nab-paclitaxel administered on this schedule showed only limited activity for patients with heavily pretreated recurrent osteosarcoma. Toxicity led to dose modifications in 33% and discontinuation in 17% of patients. When compared to a historical retrospective study, the substitution of nab-paclitaxel for docetaxel did not appear to increase activity or decrease toxicity for this patient population. Clinical trial information: NCT02945800.
Enrichment of high-risk innate immune cells in Hispanic and Black children with B-acute lymphoblastic leukemia.
Authors: Julie R. Gilbert, Himalee S. Sabnis, Roman Radzievski, Deon Doxie, Deborah DeRyckere, Sharon M. Castellino, Kavita M. Dhodapkar
Journal: Journal of Clinical Oncology (2022)

7021 Background: Black and Hispanic children with B-acute lymphoblastic leukemia (B-ALL) experience worse outcomes compared to their non-Hispanic white (NHW) counterparts. Immune-based therapies have improved the outcomes of children with B-ALL, however, impact of racial/ethnic background on immune microenvironment is less studied. Methods: BM from 61 children with newly diagnosed B-ALL(Hispanic = 21, Black = 17, NHW = 23) was obtained via the Aflac Biorepository. High-dimensional analysis was performed utilizing single cell mass cytometry with 61 markers to characterize T, NK and myeloid cells. Data was analyzed using Cytobank and high-dimensional visualization platforms such as ViSNE. Clinical data including self-reported race/ethnicity and NCI-risk classification were obtained for all samples. Results: Multi-dimensional analysis was carried out for each cell population to dissect race/ethnicity-associated differences. ViSNE clustering of NK cells identified 3 different NK populations, including a distinct population of mature CD57+ NK cells with Tbet hi , HLADR hi , granzymeB hi , CD27- phenotype. The distribution of NK subsets was highly impacted by race/ethnicity. Hispanic (H) patients had higher proportions of CD57+ mature NK cells when compared with other groups, (40 ± 4% vs 33 ± 2%; p = 0.03) with pronounced differences apparent within standard risk (SR) patients. H-SR had higher proportion of CD57+ NK cells compared to other SR patients (mean H-SR 43.4 ± 5.87% vs 26.3 ± 2.87% p = 0.0049). ViSNE clustering of myeloid cells identified 5 clusters based on patterns of cell surface markers, including a distinct CD11c+CD16+DR hi inflammatory/non-classical myeloid population. Further analysis showed that NHW-SR patients have significantly lower proportions of CD16+DR+ myeloid cells compared to Hispanic, Black and NHW-HR patients (mean NHW-SR 3.67 ± 2.56% vs Others 10.8 ± 7.87% p = 0.0394). Notably, a phenotypically similar population has recently been implicated in leukemic progression in preclinical models (Witkowski et al, Cancer Cell 2020). In contrast to innate cells, T cell clusters were broadly comparable between different racial/ethnic groups. Conclusions: These studies provide detailed single-cell proteomic analysis and highlight the impact of racial/ethnic background on immune microenvironment in pediatric B-ALL. Our data identify differences in innate immunity with enrichment of high-risk immune-populations in Hispanic and Black children and depletion of inflammatory myeloid populations in NHW-SR children with B-ALL. These variations may contribute to the observed differences in outcomes and may impact application of immune therapies in racial/ethnic groups.
Blood-based miRNA, exosomal PD-L1, and immune profiling analysis as predictive biomarkers for immune checkpoint inhibitor treatment response in urothelial cancer.
Authors: Joori Kim, In-Ho Kim, Sun Shin, Ok Ran Kim, Juyeon Park, Nahyeon Kang, Kabsoo Shin
Journal: Journal of Clinical Oncology (2022)

e16559 Background: Predicting response to immune checkpoint inhibitor (ICI) is difficult and adequate biomarkers are lacking. PD-L1 expression of tumor cells (TC) and tumor-infiltrating immune cells (IC) has limitations. We hypothesized that peripheral blood analysis would provide systemic insights about the immune responses induced by therapies blocking the PD-1/PD-L1 pathway. Methods: First, plasma samples from urothelial cancers (N = 30) with matched paired samples (N = 27) at baseline, after 1 week of PD-L1 inhibitor administration, and at response evaluation were analyzed. Exosomes were extracted and the expression of plasma-derived exosomal PD-L1 (exo PD-L1) and cytokine levels (IFN-γ, IL-10, TGF-ß, granzyme B) were determined with ELISA. Peripheral blood mononuclear cells (PBMCs) were analyzed with FACS. Samples were stained with anti-CD3, CD8, CD69, and PD1. Secondly, small RNA-sequencing was done using plasma samples from 8 patients and samples from 4 normal ones to identify differentially expressed miRNAs (DE-miRNAs) between treatment responders and non-responders. Expressions of selected DE-miRNAs were validated in a separate patient cohort of 54 patients. Results: In all of patients’ samples tested, exoPD-L1 was detected. Pretreatment level of exoPD-L1 was significantly higher in patients with objective tumor response (P = 0.010). For both clinical responders and non-responders, the level of exoPD-L1 expression increased at treatment day 8. A lower fold change (&lt; 18) in plasma exoPD-L1 was associated with a better rate of response to the anti-PD-L1 therapy (P = 0.032). Compared to non-responder group, the PD1+CD8+T-cell fraction was significantly lower at baseline (p = 0.005) and increased at treatment day 8 in the responder group (p = 0.018). At baseline, the IL-10 level was significantly higher in the responder group (p = 0.005). Decreased levels of immune-suppressive cytokines, TGF-beta1/2 and IL-10, at post-treatment day 8 indicated better response (p = 0.005 and 0.020, respectively). From small RNA sequencing analysis, two upregulated (miR-451a and let-7i-5p) and eight downregulated (miR-1290, miR-151a-3p, miR-10b-5p, miR-148a-3p, miR-10a-5p, miR-1246, miR-34c-3p, let-7b-3p) differentially expressed miRNA in responders were identified. Conclusions: Our findings suggested that the higher expression of exoPD-L1, early peripheral PD1+CD8+T-cell response, and decrease of immunosuppressive cytokines could serve as blood-based predictive biomarkers for responses to ICI treatment and that miRNAs could act as regulators in these processes.
Pan-Cancer analysis of the mutation frequency of genes in DDR pathway in Chinese population.
Authors: Zhe Zhang, Zhuoqi Li
Journal: Journal of Clinical Oncology (2022)

e15109 Background: The DNA damage repair (DDR) pathway is of vital importance to maintain human genomic stability. And the variation of DDR pathway related genes is closely related to tumorigenesis, tumor progression and therapeutic response. In order to comprehensively study the mutation status of DDR pathway related genes in human cancers, we evaluated the genomic features of Chinese pan-cancer patients and investigated the mutation frequency of genes in DDR pathway. Methods: A total of 5018 patients consisting of more than 22 cancer types were enrolled in this study. Utilizing target next-generation sequencing (NGS) platform, genomic profiling of 599 cancer-related genes was performed on tumor tissue or blood samples. And many DDR pathway related genes are included and detected mutations such as TP53, BRCA2, BRCA1, ATM, BLM, FANCA, POLE and so on. Results: We observed 91.23% (4578/5018) of cases harbored at least one alteration of the DDR pathway genes. The mutation frequency ranges from 71.88% to 100.00% among the 22 cancer types. Among them the DDR gene mutation frequency of lymphoma, esophagus and esophagogastric junction cancer and endometrial cancer are all 100%, and mutation frequency of bowel cancer, hepatobiliary cancer, melanoma, breast cancer, esophageal cancer, gastric cancer and central nervous system cancer are also more than 90% respectively. The highest mutation rate gene is a well-known tumor suppressor gene TP53, which mutated in 2650 patients and the mutation rate is 52.81%. And it primarily mutated in esophageal cancer, with a mutation rate of 81.43%. Besides the mutation rate of TP53 in gastric cancer, bowel cancer, breast cancer, ovarian cancer, pancreatic cancer, bladder cancer and hepatobiliary cancer are all more than 50%. Followed by is BRCA2 gene, which is also a tumor suppressor gene and the mutation rate is 16.04%. Next is ATM, BLM and FANCA, the mutation rate of which is 11.68%, 11.12% and 8.97% respectively. Conclusions: We find a unique genomic feature of DDR pathway in the comprehensively analysis of the mutation profile of the Chinese pan-cancer patients, which may provide potential therapeutic targets in the future.
Risk of second primary malignancies among appendiceal cancer survivors in the United States.
Authors: Krista Michelle Wong, Seshma Ramsawak, Hasan Abuamsha
Journal: Journal of Clinical Oncology (2022)

e15514 Background: Appendiceal cancer (AC) survival rates have improved over the last decade. The risk of second primary malignancy (SPM) in AC survivors has become an important concern. Therefore, this study aimed to estimate the risk of SPM in patients with primary AC. Methods: We performed a retrospective cohort study of patients ≥18 years of age diagnosed with AC between 2000-2016 using data extracted from the United States Surveillance, Epidemiology, and End Results (SEER) database. The study endpoint was the occurrence of SPM diagnosed after two months of the index AC. We calculated the standardized incidence ratio (SIR) with 95% confidence intervals (CI) for SPM in AC survivors by using the SEER software. Results: Of 9578 patients with AC, 598 (6.2%) developed a SPM. The overall risk of SPM for all sites was significantly increased in AC patients (SIR = 1.46, 95% CI 1.34-1.58). The highest risk of developing a SPM was seen in ages &lt; 60 years, females, and Asian/Pacific Islanders, respectively (SIR = 1.84, 95% CI 1.64-2.07; SIR = 1.55, 95% CI 1.38-1.74; SIR = 1.72, 95% CI 1.12-2.52). The SPM sites associated with increased incidences included the small intestine, followed by the appendix, splenic flexure of the colon, and peritoneum/omentum/mesentery. There was an increased risk of developing non-Hodgkin lymphoma, but no elevated risk with developing second leukemias. Surgery and chemotherapy were associated with an increased incidence risk of SPM, respectively (SIR = 1.45, 95% CI 1.33-1.57; SIR = 1.47, 95% CI 1.25-1.71). Conclusions: AC survivors have an increased incidence of developing SPM, most notably in the small intestine, which suggests a pathophysiological process affecting derivatives of similar embryological origin. Long-term surveillance for SPM is recommended for AC survivors, especially those at high risk.[Table: see text]
CA-4948 for the treatment of melanoma brain metastasis.
Authors: Bently Patrick Doonan, Christina Von Roemeling, Kelena Klippel, Lan Hoang-Minh, Duane Anthony Mitchell
Journal: Journal of Clinical Oncology (2022)

2011 Background: Melanoma is a growing clinical health concern where the incidence has doubled over the last 30 years. A major driver of melanoma associated deaths is the development of brain metastases (MBM). It is estimated that 40-60% of patients with metastatic melanoma will develop MBM. Current treatment strategies have a great local control rate, but do not prevent recurrent disease, with a distant intracranial failure rate of 50% at 1 year. Novel treatments and an improved understanding of the MBM tumor microenvironment are needed. Toll-like receptor signaling is activated in cutaneous melanoma, triggering innate inflammatory activation downstream through the adapter proteins MyD88 and interleukin (IL)-1 receptor-associated kinase (IRAK-1 and -4). Increased expression of IRAK-4 stimulates transcription of multiple cellular kinases and transcription factors, and production of inflammatory chemokines and cytokines. This places IRAK-4 as a central driver of both intrinsic tumorigenicity and immune evasion in melanoma. In this study we examine IRAK-4 activation in MBM, as well as preclinical responsiveness to CA-4948, an oral first-in-class small molecule inhibitor of IRAK-4 that has demonstrated clinical activity and has an acceptable safety in cancer patients. Methods: Using multiparameter IHC and proteomics analysis IRAK-1, IRAK-4, and NF-κB pathway activation were examined in patient MBM tissues and compared to normal controls. Plasma, cerebrospinal fluid, and brain tissue were assessed via UPLC-MS/MS for CA-4948 drug concentration following single oral high dose in a murine model. Using an aggressive preclinical model of MBM, B16F10, downstream biomarker response to treatment including phospho-NF-κB, phospho-ERK1/2, and phospho-P38 was measured in control and CA-4948 treated animals using multi-parameter IHC. Survival response was also tested using the B16F10 model. Results: Our data confirm elevated IRAK-1, IRAK-4, and NF-κB signaling in patient MBM. We also demonstrate that CA-4948 is capable of achieving therapeutically relevant concentrations in the brain parenchyma, and shows single agent activity in an aggressive preclinical model of MBM. We further confirm decreased ERK1/2, MAPK and NF-κB activation in response to CA-4948 treatment. Conclusions: We present here for the first time that IRAK-4 is a strong candidate for targeted therapy in MBM. We further validate CNS penetrance of the oral IRAK-4 inhibitor CA-4948, where single agent markedly reduces the proliferative capacity of aggressive preclinical MBM, resulting in improved survival. These data warrant further investigation of CA-4948 for the treatment of melanoma brain metastases, with far reaching potential as an adjunct to standard of care.